Efficacy of sacituzumab govitecan (SG) in locally advanced (LA) or metastatic urothelial cancer (mUC) by trophoblast cell surface antigen 2 (Trop-2) expression.
Authors: Yohann Loriot, Arjun Vasant Balar, Daniel P. Petrylak, Arash Rezazadeh, Petros Grivas, Aude Flechon, Rohit K. Jain, Neeraj Agarwal, Manojkumar Bupathi, Philippe Barthelemy, Philippe Beuzeboc, Phillip Lee Palmbos, Christos Kyriakopoulos, Damien Pouessel, Cora N. Sternberg, Julia Tonelli, Emon Elboudwarej, Lauri Diehl, Juliane Margarete Jürgensmeier, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2023)

4579 Background: Patients (pts) with mUC have an estimated 5-year overall survival (OS) rate of 14%. Trop-2 is a transmembrane glycoprotein with elevated expression in many cancers, including UC. SG is a Trop-2–directed antibody-drug conjugate with accelerated FDA approval for pts with LA unresectable or mUC who previously received platinum (PT) and a checkpoint inhibitor (CPI). SG has demonstrated activity in 3 phase 2 TROPHY-U-01 mUC cohorts: Cohort 1 (C1), 28% objective response rate (ORR); Cohort 2 (C2), 32% ORR; and Cohort 3 (C3), 41% ORR. Here, we assess efficacy outcomes in C1-3 by Trop-2 archival tumor expression. Methods: Pts (≥18 years) with previously treated (PT [C3], CPI [C2], or both [C1]) LA or mUC received SG (10 mg/kg IV) on D1 and D8 of 21-D cycles; C3 pts also received pembrolizumab (200 mg) on D1 of 21-D cycles. The primary endpoint was ORR by independent review. Archival tumor samples collected at enrollment were assessed for Trop-2 protein expression using SP295 anti–Trop-2 antibody by IHC with assessment by histological scores (H-scores; scale, 0-300) and % of membrane-positive tumor cells (Roche Tissue Services). Trop-2 association with clinical endpoints was evaluated using unstratified Cox proportional hazards models for survival data and logistic regression for ORR. Results: At data cutoff, 192 pts were enrolled in C1-3; 144 pts (75%) had samples evaluable for Trop-2 prevalence and 139 pts (72%) were evaluable for efficacy analysis by Trop-2 expression (5 pts not assigned to any cohort were excluded). Baseline characteristics for pts with evaluable samples were consistent with the overall population. Median (IQR) Trop-2 H-score and % of membrane-positive tumor cells for evaluable pt samples were 215 (180-247) and 92% (75-98), respectively; these readouts were highly correlated (ρ=0.82, P&lt;0.001). ORRs for C1 samples with below (n=42) and above (n=45) median Trop-2 H-scores were 24% and 29% ( P=0.59), respectively; median progression-free survival (PFS) was 3.4 and 6.7 months (HR=0.765, P=0.262), respectively; and median OS was 9.9 and 10.9 months (HR=0.978, P=0.927), respectively. Median PFS for C1 samples with below and above median Trop-2 membrane positivity were 3.9 and 6.2 months (HR=0.835, P=0.443), respectively. Analyses of efficacy endpoints for C2 and C3 pt samples by Trop-2 expression were consistent with C1 results. Conclusions: In this analysis of archival tumor samples from pts with pretreated LA or mUC, Trop-2 protein was highly expressed across cohorts, supporting prior Trop-2 expression analyses in UC. Similar outcomes were observed between C1 pts with samples that were below and above median Trop-2 H-score with most pronounced numerical differences observed for PFS. These results suggest that SG activity may be independent of Trop-2 expression in UC, but additional studies are needed to confirm these results. Clinical trial information: NCT03547973 .